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Using a fragment of the matrix protein fibronectin (FN) to activate the \u03b15\u03b21 integrin in primary human chondrocytes, we found that endocytosis of the integrin and FN fragment complex drove the production of the matrix metalloproteinase MMP-13. Activation of \u03b15\u03b21 by the FN fragment, but not by intact FN, was accompanied by reactive oxygen species (ROS) production initially at the cell surface, then in early endosomes. These ROS-producing endosomes (called redoxosomes) contained the integrin-FN fragment complex, the ROS-producing enzyme NADPH oxidase 2 (NOX2), and SRC, a redox-regulated kinase that promotes MMP-13 production. In contrast, intact FN was endocytosed and trafficked to recycling endosomes without inducing ROS production. Articular cartilage from patients with osteoarthritis showed increased amounts of SRC and the NOX2 complex component p67\n            <jats:sup>phox<\/jats:sup>\n            . Furthermore, we observed enhanced localization of SRC and p67\n            <jats:sup>phox<\/jats:sup>\n            at early endosomes, suggesting that redoxosomes could transmit and sustain integrin signaling in response to matrix damage. This signaling mechanism not only amplifies the production of matrix-degrading proteases but also establishes a self-perpetuating cycle that contributes to the ongoing degradation of cartilage matrix in osteoarthritis.\n          <\/jats:p>","DOI":"10.1126\/scisignal.adf8299","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T17:59:05Z","timestamp":1698775145000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":38,"title":["Redox-active endosomes mediate \u03b15\u03b21 integrin signaling and promote chondrocyte matrix metalloproteinase production in osteoarthritis"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6203-2129","authenticated-orcid":true,"given":"Michael Z.","family":"Miao","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, School of Medicine, University of 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